Claims:

1. A pharmaceutical composition in the form of a solid dosage for oral
administration, the composition comprising a core comprising
phenylephrine or a pharmaceutically acceptable salt thereof in a
sustained release matrix and further comprising one or more hydrophilic
or hydrophobic polymers outside the core.

3. The composition according to claim 1, wherein the core displays
increased resistance to disintegration and erosion in the
gastrointestinal tract to allow for sustained release of the
phenylephrine or a pharmaceutically acceptable salt thereof for at least
an 8 hour time period.

4. The composition according to claim 1, wherein the core displays
increased resistance to disintegration and erosion in the
gastrointestinal tract for sustained release of the phenylephrine or a
pharmaceutically acceptable salt thereof for at least a 12 hour time
period.

5. The composition according to claim 1, wherein the core displays
increased resistance to disintegration and erosion in the
gastrointestinal tract for sustained release of the phenylephrine or a
pharmaceutically acceptable salt thereof for at least a 24 hour time
period.

6. The composition according to claim 1, wherein the hydrophilic or
hydrophobic polymers are selected from the group consisting of water
soluble cellulosic ethers, polyethylene oxide, and mixtures thereof.

7. The composition according to claim 1, further comprising one or more
pharmaceutically acceptable excipients.

8. The composition of claim 5, wherein the water soluble cellulosic ether
is selected from the group consisting of methylcellulose,
hydroxypropylcellulose, hydroxymethylcellulose,
hydroxypropylmethylcellulose, hydroxyethylcellulose,
carboxymethylcellulose, carboxyethylcellulose and mixtures thereof.

10. The composition of claim 1, wherein the phenylephrine or a
pharmaceutically acceptable salt thereof comprises approximately 1 to 25%
of the tablet weight, and the hydroxypropyl methylcellulose comprises
approximately 10 to 50% of the tablet weight.

11. The composition of claim 1, wherein the composition is stable under
standard pharmaceutical storage conditions for at least two years.

12. A pharmaceutical composition formulated for sustained release of
therapeutically effective phenylephrine dose for at least eight hours
after a single dose is administered to a human subject, the composition
comprising phenylephrine within a polymer matrix, wherein the composition
exhibits a mean AUC and/or Cmax in the human subject equivalent to
80% to 125% of the AUC and/or Cmax obtained when two doses of a
standard immediate release formulation comprising 10 mg of phenylephrine
is administered.

13. A pharmaceutical composition formulated for sustained release of
therapeutically effective phenylephrine dose for at least twelve hours
after a single dose is administered to a human subject, the composition
comprising phenylephrine within a sustained release polymer matrix,
wherein the composition exhibits a mean AUC and/or Cmax in the human
subject equivalent to 80% to 125% of the AUC and/or Cmax obtained
when three doses of a standard immediate release formulation comprising
10 mg of phenylephrine is administered.

14. A pharmaceutical composition formulated for sustained release of
therapeutically effective phenylephrine dose for at least twenty four
hours after a single dose is administered to a human subject, the
composition comprising phenylephrine within a polymer matrix, wherein the
composition exhibits a mean AUC and/or Cmax in the human subject
equivalent to 80% to 125% of the AUC and/or Cmax obtained when six
doses of a standard immediate release formulation comprising 10 mg of
phenylephrine is administered.

15. A pharmaceutical composition comprising phenylephrine or a
pharmaceutically acceptable salt thereof in a sustained release polymer
matrix, wherein said composition when administered once to a subject
exhibits a mean AUC and/or Cmax which is at least 80% of the mean
AUC and/or Cmax exhibited by two doses of a pharmaceutical
composition containing 10 mg of phenylephrine and no sustained release
polymer matrix.

16. A pharmaceutical composition comprising phenylephrine or a
pharmaceutically acceptable salt thereof in a sustained release polymer
matrix, wherein said composition when administered once to a subject
exhibits a mean AUC and/or Cmax which is at least 80% of the mean
AUC and/or Cmax exhibited by three doses of a pharmaceutical
composition containing 10 mg of phenylephrine and no sustained release
polymer matrix.

17. A pharmaceutical composition comprising phenylephrine or a
pharmaceutically acceptable salt thereof in a sustained release polymer
matrix, wherein said composition when administered once to a subject
exhibits a mean AUC and/or Cmax which is at least 80% of the mean
AUC and/or Cmax exhibited by six doses of a pharmaceutical
composition containing 10 mg of phenylephrine and no sustained release
polymer matrix.

23. A pharmaceutical composition comprising phenylephrine or a
pharmaceutically acceptable salt thereof, wherein the composition
exhibits an sustained release of phenylephrine from the composition when
contacted with USP simulated intestinal fluid.

24. The pharmaceutical composition of claim 23 that provides a sustained
release for a period of at least 8 hours such that a determination can be
made that less than the total amount of phenylephrine has been dissolved
in the USP simulated intestinal fluid over said time period.

25. A pharmaceutical composition comprising phenylephrine or a
pharmaceutically acceptable salt thereof, wherein the composition
exhibits an sustained release of phenylephrine from the composition when
contacted with USP simulated intestinal fluid, such that no more than 30
percent of the phenylephrine or pharmaceutically acceptable salt thereof
is released from the pharmaceutical composition within one hour, no more
than 60 percent of the phenylephrine or pharmaceutically acceptable salt
thereof is released from the pharmaceutical composition within four
hours, no more than 90 percent of the phenylephrine or pharmaceutically
acceptable salt thereof is released from the pharmaceutical composition
within about 8 hours, and at least 99 percent of the phenylephrine or
pharmaceutically acceptable salt thereof is released from the
pharmaceutical composition within about 24 hours.

Description:

[0002]Phenylephrine and its pharmaceutically acceptable salts are
recognized as safe and effective nasal decongestants. Commercially
available formulations include nasal jelly, nasal drops, and nasal spray
(i.e. Alconefrin® Nasal Drops or Neo-Synephrine® Nasal Jelly) as
well as immediate release oral tablets or gelatin capsules (i.e. Sudafed
PE® or DayQuil® LiquiCaps). Phenylephrine or a pharmaceutically
acceptable salts as currently formulated is commonly administered every
four hours for the relief of nasal congestion due to the short half-life
of phenylephrine. Thus, there is a need for sustained release
formulations of phenylephrine that can be administered less frequently,
for example, once every eight hours, every twelve hours or possibly every
twenty four hours.

[0003]Sustained release formulations result in a decrease in the frequency
of drug administration thereby improving patient compliance. In addition,
sustained drug release systems produce constant therapeutic plasma levels
of active ingredients as compared to fluctuations seen when multiple
doses of a conventional formulation are given. Sustained drug release may
decrease the severity and frequency of side effects from multiple dosages
or from pulsed release systems.

[0004]U.S. Pat. No. 4,792,452 discloses a tablet formulation composed of
up to about 45% by weight of a pH-dependent salt of alginic acid, up to
about 35% by weight of a pH-independent hydrocolloid gelling agent,
binder and excipients. Release of the drug is therefore affected by the
varying pH of the gastrointestinal tract. Australian patent application
AU-B-56761/86 discloses examples of sustained release formulations for
aspirin and theophylline including specific
hydroxypropylmethylcelluloses. AU-B-56761/86 also describes phenylephrine
as one of at least twenty-seven drugs or types of drugs that are typical
moisture sensitive drugs. JP 2005-60294 discloses stabilized compositions
of phenylephrine containing carbinoxamine and various salts.

[0005]A decongestant is commonly administered orally in combination with
an antihistamine for relieving nasal congestion associated with allergic
rhinitis. Antihistamines with long half lives compared to phenylephrine
are known. When the decongestant is phenylephrine or its pharmaceutically
acceptable salt, and the antihistamine is a long-acting antihistamine,
then the dosage form should preferably be designed such that the long
acting antihistamine is released in a conventional manner and
phenylephrine is released at a sustained rate such that the
pharmaceutical composition is suitable for eight hour or longer
administration.

[0006]Loratadine is disclosed in U.S. Pat. No. 4,282,233 as a non-sedating
antihistamine useful, for example, in alleviation of seasonal allergic
rhinitis symptoms such as sneezing and itching, and in the treatment of
chronic idiopathic urticaria in patients six years or older. Loratadine
is available in the form of conventional tablets that release loratadine
in a conventional manner by the processes of disintegration and
dissolution such that loratadine begins to elicit its antihistaminic
effect within 1 to 3 hrs and the effect lasts in excess of 24 hrs. The
tablets are thus orally administered only once daily. Azatadine is
disclosed in Belgian Patent No. 647,043 and in corresponding U.S. Pat.
Nos. 3,326,924 and 3,419,565. The elimination half-life is reported to be
9-12 hrs. Terfenadine and fexofenadine are disclosed in U.S. Pat. No.
3,878,217 and have a duration of action of 12 to 24 hrs, and greater than
24 hrs., respectively. Cetirizine disclosed in U.S. Pat. No. 4,525,358;
astemizole in U.S. Pat. No. 4,219,559, and levocabastine in U.S. Pat. No.
4,369,184; have a duration of action of 12 to 24 hrs, greater than 24
hrs, and 16 to 24 hrs; respectively.

[0007]It is an object of the present invention to provide an oral
sustained release pharmaceutical composition that releases phenylephrine
or a pharmaceutically acceptable salt thereof over a period of at least
eight hours, preferably at least 12 hours, more preferably at least 24
hours.

[0008]It is another object of the invention to provide a pharmaceutical
composition that provides for combined administration in a single dose
form of a therapeutically effective amount of phenylephrine or
pharmaceutically acceptable salt thereof and an additional therapeutic
composition, such as an antihistamine, that has a natural half-life
longer than phenylephrine.

[0009]These and other objectives of the invention are satisfied by the
invention described and claimed below, which provides a single dose of
phenylephrine to achieve a distribution over at least eight hours. As
described in the examples below, one embodiment of the invention has been
demonstrated to provide a single dose of phenylephrine that is
bioequivalent to two doses of immediate release phenylephrine given at
four hour intervals. Additionally, formulations prepared according to the
invention are stable, with a shelf life of at least two years.
Formulations according to the invention may comprise phenylephrine alone
or phenylephrine in combination with additional pharmaceutically active
agents, including antihistamines, analgesics, and others.

SUMMARY OF THE INVENTION

[0010]Thus, the invention provides a pharmaceutical composition in the
form of a solid dosage for oral administration, the composition
comprising a core comprising phenylephrine or a pharmaceutically
acceptable salt thereof in a sustained release matrix, and further
comprising one or more hydrophilic or hydrophobic polymers outside the
core.

[0011]The invention further provides a pharmaceutical composition
formulated for sustained release of therapeutically effective
phenylephrine dose for at least eight hours after a single dose is
administered to a human subject, the composition comprising phenylephrine
within a polymer matrix comprising hydroxypropyl methylcellulose, wherein
the composition exhibits a mean AUC and/or Cmax in the human subject
equivalent to 50% to 125% of the AUC and/or Cmax obtained when two
doses of a standard immediate release formulation comprising 10 mg of
phenylephrine is administered. In a preferred embodiment, the composition
exhibits a mean AUC and/or Cmax in the human subject equivalent to
80% to 125% of the AUC and/or Cmax obtained when two doses of a
standard immediate release formulation comprising 10 mg of phenylephrine
is administered.

[0012]The invention further provides a pharmaceutical composition
formulated for sustained release of therapeutically effective
phenylephrine dose for at least twelve hours after a single dose is
administered to a human subject, the composition comprising phenylephrine
within a polymer matrix comprising hydroxypropyl methylcellulose, wherein
the composition exhibits a mean AUC and/or Cmax in the human subject
equivalent to 50% to 125% of the AUC and/or Cmax obtained when three
doses of a standard immediate release formulation comprising 10 mg of
phenylephrine is administered. In a preferred embodiment, the composition
exhibits a mean AUC and/or Cmax in the human subject equivalent to
80% to 125% of the AUC and/or Cmax obtained when three doses of a
standard immediate release formulation comprising 10 mg of phenylephrine
is administered.

[0013]The invention also provides a pharmaceutical composition formulated
for sustained release of therapeutically effective phenylephrine dose for
at least twenty four hours after a single dose is administered to a human
subject, the composition comprising phenylephrine within a polymer matrix
comprising hydroxypropyl methylcellulose, wherein the composition
exhibits a mean AUC and/or Cmax in the human subject equivalent to
50% to 125% of the AUC and/or Cmax obtained when six doses of a
standard immediate release formulation comprising 10 mg of phenylephrine
is administered. In a preferred embodiment, the composition exhibits a
mean AUC and/or Cmax in the human subject equivalent to 80% to 125%
of the AUC and/or Cmax obtained when six doses of a standard
immediate release formulation comprising 10 mg of phenylephrine is
administered.

[0014]The invention also provides a pharmaceutical composition comprising
phenylephrine or a pharmaceutically acceptable salt thereof in a
sustained release polymer matrix, wherein said composition when
administered once to a subject exhibits a mean AUC and/or Cmax which
is at least 50% of the mean AUC and/or Cmax exhibited by two doses
of a pharmaceutical composition containing 10 mg of phenylephrine and no
sustained release polymer matrix. In a preferred embodiment, the
composition when administered once to a subject exhibits a mean AUC
and/or Cmax which is at least 80% of the mean AUC and/or Cmax
exhibited by two doses of a pharmaceutical composition containing 10 mg
of phenylephrine and no sustained release polymer matrix.

[0015]The invention further provides a pharmaceutical composition
comprising phenylephrine or a pharmaceutically acceptable salt thereof in
a sustained release polymer matrix, wherein said composition when
administered once to a subject exhibits a mean AUC and/or Cmax which
is at least 50% of the mean AUC and/or Cmax exhibited by three doses
of a pharmaceutical composition containing 10 mg of phenylephrine and no
sustained release polymer matrix. In a preferred embodiment, the
composition when administered once to a subject exhibits a mean AUC
and/or Cmax which is at least 80% of the mean AUC and/or Cmax
exhibited by three doses of a pharmaceutical composition containing 10 mg
of phenylephrine and no sustained release polymer matrix.

[0016]The invention also provides a pharmaceutical composition comprising
phenylephrine or a pharmaceutically acceptable salt thereof in a
sustained release polymer matrix, wherein said composition when
administered once to a subject exhibits a mean AUC and/or Cmax which
is at least 50% of the mean AUC and/or Cmax exhibited by six doses
of a pharmaceutical composition containing 10 mg of phenylephrine and no
sustained release polymer matrix. In a preferred embodiment, the
composition when administered once to a subject exhibits a mean AUC
and/or Cmax which is at least 80% of the mean AUC and/or Cmax
exhibited by six doses of a pharmaceutical composition containing 10 mg
of phenylephrine and no sustained release polymer matrix.

[0017]The invention further provides a pharmaceutical composition
comprising phenylephrine or a pharmaceutically acceptable salt thereof,
wherein the composition exhibits an sustained release of phenylephrine
from the composition when contacted with USP simulated intestinal fluid,
such that no more than 30 percent of the phenylephrine or
pharmaceutically acceptable salt thereof is released from the
pharmaceutical composition within one hour, no more than 60 percent of
the phenylephrine or pharmaceutically acceptable salt thereof is released
from the pharmaceutical composition within four hours, no more than 90
percent of the phenylephrine or pharmaceutically acceptable salt thereof
is released from the pharmaceutical composition within about 8 hours, and
at least 99 percent of the phenylephrine or pharmaceutically acceptable
salt thereof is released from the pharmaceutical composition within about
24 hours.

BRIEF DESCRIPTION OF THE DRAWINGS

[0018]FIG. 1: Release profile of phenylephrine HCl from a tablet was over
a 24 hour time period. The dissolution study was conducted with USP
simulated intestinal fluid using an USP Apparatus II stirring set at 50
rpm. At each time interval, a sample of the solution was analyzed to
determine the percent of phenylephrine HCl dissolved.

[0019]FIG. 2: Mean plasma concentration over 24 hours from a
bioequivalence study comparing a single dose of 30 mg phenylephrine in a
tablet according to the invention (Test Product B) to two 10 mg
phenylephrine immediate release tablets (Reference Product S) dosed four
hours apart.

[0020]FIG. 3: Mean plasma concentration over 24 hours on a
semi-logarithmic scale from a bioequivalence study comparing a single
does of 30 mg phenylephrine in a tablet according to the invention (Test
Product B) to two 10 mg phenylephrine immediate release tablets
(Reference Product S) dosed four hours apart.

DETAILED DESCRIPTION OF THE INVENTION

[0021]The present invention provides a pharmaceutical composition in the
form of a solid dosage comprising phenylephrine or a pharmaceutically
acceptable salt and one or more sustained release polymers together with
excipients to provide a composition that releases phenylephrine over a
period of about eight or more hours. The composition according to the
invention is bioequivalent to at least two standard release dosage forms
given four hours apart when measured by Cmax and AUC for serum
analysis in human subjects. In a preferred embodiment, the invention is
bioequivalent to at least three standard release dosage forms given four
hours apart when measured by Cmax and AUC for serum analysis in
human subjects. In a further preferred embodiment, the composition
according to the invention is bioequivalent to at least six standard
release dosage forms given four hours apart when measured by Cmax
and AUC for serum analysis in human subjects.

[0022]As used herein in relation to a preferred embodiment, the term
bioequivalent is used according to its commonly understood meaning, i.e.,
a composition exhibiting between 80% and 125% of the Cmax and AUC
for serum analysis in human subjects of a standard release dosage form.

[0023]According to one embodiment of the invention, an amount of
phenylephrine is formulated for sustained release within a tablet core.
As used herein, the term sustained release refers to release of the
active agent from the pharmaceutical composition so that it becomes
available for bio-absorption in the subject, primarily in the
gastrointestinal tract of the subject, over a prolonged period of time,
such as about 1 hour to 24 hours or more. In certain embodiments of the
composition of the invention, that period of time will be at least about
8 hours, at least about 12 hours, or at least about 24 hours. The term
sustained release also encompasses what is otherwise referred to as
extended release, controlled release, or sustained delivery. The release
rate of the active agent is primarily controlled by dissolution of the
active agent in gastrointestinal fluid and subsequent diffusion out of
the tablet independent of pH, but can also be influenced by physical
processes of disintegration and erosion of the tablet. Due to the
relatively short half life of phenylephrine, therapeutic blood serum
concentrations of phenylephrine are primarily a result of release of
phenylephrine from the tablet over a prolonged period of time.
Formulations according to the invention provide a single dose of
phenylephrine to achieve a therapeutic blood serum concentration of
phenylephrine in a subject in need thereof for an extended period of time
so as to provide for a therapeutic effect of phenylephrine in the
subject. In separately preferred embodiments of this invention,
phenylephrine is released from the tablet to result in a therapeutic
blood serum concentration for at least 8 hours, or at least 12 hours or
at least 24 hours from a single dose. The release rate from the tablet is
independent of pH, but is highly dependent on the solubility profile for
phenylephrine. Active agents other than phenylephrine have different
release rates than phenylephrine, and therefore are not predictive for
compositions according to the invention.

[0024]In a preferred embodiment, phenylephrine is used in combination with
an additional active ingredient. When phenylephrine is used in
combination with an antihistamine, the antihistamines can be of H1
or H2 antagonists or other types of histamine release inhibitors.
The H1 antagonists can be sedating or non-sedating, such as
diphenhydramine, chlorpheniramine, tripelennamine, promethazine,
clemastine, doxylamine, astemizole, terfenadine, and loratadine, among
others. Examples of H2 antagonists include, but are not limited to,
cimetadine, famotidine, nizatidine, and ranitidine. Examples of
histamine-release-inhibitors include, but are not limited to, cromolyn.

[0025]If the optional active ingredient(s) used has similar water
solubility to phenylephrine, it can located within the core of the
tablet, i.e., within the polymer matrix for controlled release. In
additional embodiments, the optional active ingredient(s) has a long
half-life compared to phenylephrine and does not require controlled
release, but rather is released at a rapid or immediate release while
phenylephrine is released at a sustained rate. In such cases, the
optional active ingredient(s) can be located outside the core of the
tablet.

[0026]The core of the tablet can also include additional inactive
pharmaceutically acceptable carrier material. The term pharmaceutically
acceptable carrier refers to any non-toxic solid, semisolid or liquid
filler, diluent, encapsulating material or formulation auxiliary of any
type. Suitable pharmaceutical carriers are described in Gennaro et al.,
(1995) Remington's Pharmaceutical Sciences, Mack Publishing Company. In a
preferred embodiment the carrier material comprises solid pharmaceutical
excipients such as starch, cellulose, talc, glucose, lactose, sucrose,
gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium
stearate, glycerol monostearate, sodium chloride, dried skim milk and the
like. In a preferred embodiment, the core of the pharmaceutical
composition of the invention further comprises lactose, which may be in
any of its pharmaceutically acceptable grades, including for example,
β-lactose, anhydrous α-lactose, α-lactose monohydrate.
In certain instances it may be important to control the water content of
the materials used in the formulation of the pharmaceutical composition,
for example to provide long term stability, for example for at least one,
two, three or more years, and/or to control microbial growth during long
term storage. In those instances, anhydrous forms of carrier materials
may be preferred.

[0027]The sustained release polymer comprising the core of the tablet is
hydroxypropyl methylcellulose. The sustained release polymer may be
present in an amount from about 15% to 50%, preferably from about 20% to
40%, more preferably from about 25% to about 35% and even more preferably
from about 29% to 31% by weight of the tablet. According to one
embodiment of the invention, the sustained release polymer comprises
hydroxypropyl methylcellulose in an amount of about 30% by total weight
of the tablet. In a preferred embodiment, the sustained release polymers
are combined with lactose as a major component of the tablet. For
example, for a tablet comprising about 30% by weight hydroxypropyl
methylcellulose and about 4% by weight hydroxypropylcellulose, about
59.5% by weight of the tablet may be lactose.

[0028]Examples of hydroxypropyl methylcellulose polymers that may be used
in the present invention include those available from Dow Chemical Co.
(Michigan, USA) under the brand name Methocel, such as, Methocel K100M
CR, Methocel K3, Methocel K15M, and the like. Hydroxypropyl
methylcellulose is also known as hypromellose.

[0029]As an example of a binder material, hydroxypropylcellulose polymers
may be used in the present invention including, for example, those
available under the brand names Klucel® from Aqualon (Delaware, USA)
such as Klucel EXF®, Klucel JF®, Klucel HF®, and Nisso HPC®
from Nippon Soda Co., Ltd. (Tokyo, Japan), such as HPC-L®, HPC-M®,
and the like. Hydroxypropylcellulose can be present in the compositions
of the invention in an amount up to about 10%, preferably up to about
7.5%, more preferably up to about 4% of the total weight of the
composition. Additional cellulose ethers may be present in the tablet,
outside the core, in addition to hydroxypropylcellulose, such as other
water soluble or swellable polymers including sodium carboxymethyl
cellulose, xanthan gum, acacia, tragacanth gum, guar gum, karaya gum,
alginates, gelatin, albumin and the like.

[0030]The dosage forms according to the invention are solid, and may take
any customary form for oral administration, such as a tablet, a pill, a
capsule, and the like. A preferred example of the solid dosage form is a
compressed tablet. Dosage forms according to the invention may further
contain standard excipients, such as disintegrants, glidants, binding
agents, and antiadherents.

[0031]A sustained release formulation of the present invention may further
comprise pharmaceutical additives including, but not limited to:
lubricants such as magnesium stearate, calcium stearate, zinc stearate,
powdered stearic acid, hydrogenated vegetable oils, talc, polyethylene
glycol, and mineral oil; colorants such as various FD&C colors; binders
such as sucrose, lactose, gelatin, starch paste, acacia, tragacanth,
povidone, polyethylene glycol, pullulan and corn syrup; glidants such as
colloidal silicon dioxide and talc; surface active agents such as sodium
lauryl sulfate, dioctyl sodium sulfosuccinate, triethanolamine,
polyoxyethylene sorbitan, poloxalkol, and quaternary ammonium salts;
preservatives and stabilizers; excipients such as lactose, mannitol,
glucose, fructose, xylose, galactose, sucrose, maltose, xylitol,
sorbitol, chloride, sulfate and phosphate salts of potassium, sodium, and
magnesium; and/or any other pharmaceutical additives known to those of
skill in the art such as microcrystalline cellulose or dicalcium
phosphate. Standard tablet excipients may be included in formulations
according to the invention.

[0032]Optionally, the blend of phenylephrine, sustained release polymer,
and excipients may be converted into granules by conventional means. For
example, a wet granulation process including alcohol may be used. In one
embodiment, tablets are manufactured by dry blending and granulating of
the active ingredient with excipients, addition of anti-oxidant agents,
chelating agents, moisture scavenging agents, or other stabilization aids
such as magnesium stearate, and control of moisture levels in the
granulated/compressed product to prevent phenylephrine degradation, use
of a coated phenylephrine salt or use of a combination manufacturing
process which separates phenylephrine salt from a wet granulation process
and incorporates the active ingredient into the process by dry
granulation or mixing. Direct compression and other conventional methods
may be used to form tablets. Optionally, the blend or the granulated
blend may be compressed into a core and coated with a polymeric film.
Stability and degradation analyses can be performed according to
International Conference on Harmonization (ICH) standards as described in
"Impurities in New Drug Products" guidelines to simulate two or more
years of shelf life. For example, stability testing can be performed at
40 degrees Celsius/75% relative humidity for a 3-month time period.
Standard pharmaceutical storage conditions are known in the art.
Compositions according to the invention can be assayed to meet all ICH
guidelines for active pharmaceutical assay with degradant levels which
are below reporting limits, preferably below identification limits, most
preferably below qualification limits.

[0033]The invention further provides a pharmaceutical composition
comprising phenylephrine or a pharmaceutically acceptable salt thereof,
wherein the composition exhibits an sustained release of phenylephrine
from the composition when contacted with USP simulated intestinal fluid.
In this aspect of the invention, the pharmaceutical composition is
formulated such that when tested in in vitro methods that simulate in
vivo conditions, the pharmaceutical composition can be analyzed to
demonstrate a sustained release of phenylephrine from the composition. In
one embodiment, the pharmaceutical composition will provide a sustained
release for a period of at least 8 hours such that a determination can be
made that less than the total amount of phenylephrine has been dissolved
in the USP simulated intestinal fluid over that time period. In
additional embodiments, the time period is at least 12 hours, at least 16
hours, at least 20 hours or at least 24 hours.

[0034]In a preferred embodiment the composition exhibits sustained release
of phenylephrine such that no more than 30 percent of the phenylephrine
or pharmaceutically acceptable salt thereof is released from the
pharmaceutical composition within one hour of contact with the USP
simulated intestinal fluid, no more than 60 percent of the phenylephrine
or pharmaceutically acceptable salt thereof is released from the
pharmaceutical composition within four hours, no more than 90 percent of
the phenylephrine or pharmaceutically acceptable salt thereof is released
from the pharmaceutical composition within about 8 hours, and at least 99
percent of the phenylephrine or pharmaceutically acceptable salt thereof
is released from the pharmaceutical composition within about 24 hours.

[0035]The subject to whom the composition according to the invention is to
be administered is not restricted. The dosage varies depending on the
size and age of the patient, the severity of the symptoms, and the like.
The administration is preferably carried out by adjusting the dosage
based on various factors taken into account by those of ordinary skill in
the art, which include the subject's age, weight, prior dose response,
and is preferably administered once or twice daily.

EXAMPLES

[0036]The present invention is illustrated by the following examples.
Alternatives will be apparent to those skilled in the art and are
considered to be within the scope of the invention, and therefore the
examples are not to be construed to restrict the invention.

[0038]Phenylephrine HCl was passed through a 30 mesh screen. Lactose
monohydrate, Methocel K100M CR, phenylephrine HCl, and Klucel EXF were
charged into a blender and blended until uniform. A portion of half of
the magnesium stearate was passed through a 30 mesh screen and added to
blender with uniform mixture, and blended for an additional 1-3 minutes.
The resulting mixture was granulated with a roller/compactor, sized with
a mill, and blended for an additional 1-3 minutes. The remaining portion
of magnesium stearate was passed through a 30 mesh screen and blended
with the mixture for 1-3 minutes. The mixture was compressed into
tablets. In an alternate procedure, the entire portion of magnesium
stearate is passed through a 30 mesh screen and charged to the mixture in
the blender in a single step. The mixture is blended for 1-3 minutes and
the resulting granules are compressed into a tablet.

Example 2

Tablet Dissolution Profile

[0039]The release profile of phenylephrine HCl from a tablet according to
Example 1 was studied over a 24 hour time period. The dissolution study
was conducted with USP simulated intestinal fluid using an USP Apparatus
II stirring set at 50 rpm. At each time interval, a sample of the
solution was analyzed to determine the percent of Phenylephrine HCl
dissolved. FIG. 1 presents the data graphically.

[0040]Bioequivalence was studied according to accepted guidelines (see
Food and Drug Administration, Guidance for Industry: Bioavailability and
Bioequivalence Studies for Orally Administered Drug Products--General
Considerations, Center for Drug Evaluation and Research, March 2003; see
also Food and Drug Administration, Statistical Approaches to Establishing
Bioequivalence, Center for Drug Evaluation and Research, January 2001).
The study compared a single dose of 30 mg phenylephrine in a tablet
according to the invention to two 10 mg phenylephrine immediate release
tablets (Sudafed PE® Nasal Decongestant Tablets 10 mg) dosed four
hours apart. Twenty-four healthy volunteers were enrolled in the study.
On study day 1, subjects were dosed at random with a single oral dose of
either the test tablet or two doses of the comparison tablet. Following a
three day washout period, subjects returned and were dosed with the
alternative treatment per randomization. Drug administration was assisted
with 240 mL of ambient temperature water.

[0042]The 90% confidence intervals about the ratio of the test geometric
mean to the reference geometric mean are within the 80% and 125% limits
for the pharmacokinetic parameters Cmax, AUC0-t, and
AUC.sub.∞, of the ln-transformed data.

[0043]Relevant parameters are understood as follows: [0044]Cmax
Peak drug concentration obtained directly from the data without
interpolation. [0045]Tmax Time to peak drug concentration obtained
directly from the data without interpolation. [0046]Ct The last
measured plasma concentration; the last concentration above the lower LOQ
following a dose. [0047]λz(kelim) Terminal or elimination
rate constant determined from the slope of the drug concentration-time
curve using linear regression on terminal data points of the curve.
[0048]AUC0-t Area under the concentration-time curve from zero to
time t, calculated by the trapezoidal rule, where t is the last time
point with measurable concentration.

[0049]AUC0-∞ Area under the concentration-time curve from time
zero to time infinity, calculated by the following:

AUC0-∞=AUC0-t+Ct/λz[0050]Where Ct
is the last measurable drug concentration and λz is the
terminal or elimination rate constant. [0051]t1/2 Terminal or
elimination half-life of the drug, calculated from the equation:

[0051]t1/2=ln(2)/λz

Example 4

Dual Release Phenylephrine Sustained Release Tablet

[0052]The following example provides a pharmaceutical formulation
comprising phenylephrine in two parts, the first part comprising an
immediate release formulation and the second part comprising between
about 18-22 mg phenylephrine in a zero order, or near zero order,
sustained release formulation. The immediate released layer could be as
active coating or an immediate released layer of a two or three layered
tablet. The zero or near zero order sustained release portion could be as
core tablet or as a layer of a two or three layered tablet.

[0053]Accordingly, the composition can comprise the following sustained
release portion and immediate release portions.

[0056]The results presented in the Examples and Figures are non-limiting.
From the above description, one can ascertain the essential
characteristics of the present invention and, without departing from the
spirit and scope thereof, can make various changes and modifications of
the invention to adapt it to various uses and conditions.